title: The consequences of long-term glycogen synthase kinase-3 inhibition on normal and insulin resistant rat hearts.
abstract: BACKGROUND
  Glycogen synthase kinase-3 (GSK-3) is a serine-threonine protein kinase, discovered as a regulator of glycogen synthase. GSK-3 may regulate the expression of SERCA-2a potentially affecting myocardial contractility. It is known to phosphorylate and inhibit IRS-1, thus disrupting insulin signalling. This study aimed to determine whether myocardial GSK-3 protein and its substrate proteins are dysregulated in obesity and insulin resistance, and whether chronic GSK-3 inhibition can prevent or reverse this.
  
  
  METHODS
  Weight matched male Wistar rats were rendered obese by hyperphagia using a special diet (DIO) for 16 weeks and compared to chow fed controls. Half of each group was treated with the GSK-3 inhibitor CHIR118637 (30 mg/kg/day) from week 12 to16 of the diet period. Biometric and biochemical parameters were measured and protein expression determined by Western blotting and specific antibodies. Ca(2+)ATPase activity was determined spectrophotometrically. Cardiomyocytes were prepared by collagenase perfusion and insulin stimulated 2-deoxy-glucose uptake determined.
  
  
  RESULTS
  DIO rats were significantly heavier than controls, associated with increased intra-peritoneal fat and insulin resistance. GSK-3 inhibition did not affect weight but improved insulin resistance, also on cellular level. It had no effect on GSK-3 expression but elevated its phospho/total ratio and elevated IRS-2 expression. Obesity lowered SERCA-2a expression and activity while GSK-3 inhibition alleviated this. The phospho/total ratio of phospholamban underscored inhibition of SERCA-2a in obesity. In addition, signs of myocardial hypertrophy were observed in treated control rats.
  
  
  CONCLUSIONS
  GSK-3 inhibition could not reverse all the detrimental effects of obesity but may be harmful in normal rat hearts. It regulates IRS-2, SERCA-2a and phospholamban expression but not IRS-1.
authors.affiliation: Department of Medicine, Division of Pharmacology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, 7505, South Africa.
authors.forename: T B
authors.initials: TB
authors.lastname: Flepisi
authors.forename: Amanda
authors.initials: A
authors.lastname: Lochner
authors.forename: Barbara
authors.initials: B
authors.lastname: Huisamen
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004032:Diet; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D055504:Insulin Receptor Substrate Proteins; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat